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Histoplasmosis and Pulmonary Tuberculosis
228
when GOWLAND HOPKINS showed that diseases may be caused, without the intervention of toxic agents, merely by deficiency in nutrients needed in minute amounts. Later research, however, has indicated that the body’s requirements for aneurine (B1) are related to the carbohydrate intake ; and on this basis the starch in polished rice might be looked on as toxic to fowls suffering from aneurine deficiency. Apart from these early surmises, MELLANBY must be given full credit for the introduction and practical ’’ proof of the toxamin theory. About 20 years ago he found that dogs whose diets contained certain cereal products---$-particularly oatmeal-were abnormally liable to rickets. BRUCE and CALLOW subsequently showed that the anti-calcifying properties of cereals were due to the presence of phytic acid, which is a phosphorylated form of the vitamin inositol. HARRISON and MELLANBY confirmed that phytic acid had the same rachitogenic effects as cereals in dogs, while McCANCE reported that calcium metabolism was disturbed in human subjects subsisting on a diet consisting largely of wholemeal bread, which is rich in phytic acid. Investigations in many other fields have since demonstrated that a wide variety of natural substances may interfere with the action of different vitamins. Thus vitamins A and E are opposed by rancid fats,- vitamin E by cod-liver oil, vitamin K by dicoumarol present in spoilt sweet clover, vitamin B1 by some forms of raw fish and by substances present in ferns, nicotinic acid by maize, and biotin by the avidin present in raw egg-white. In addition to these natural antagonists many artificial anti-vitamins have been synthesised. The first representatives of this class to be discovered were the sulphonamides, which were used in infections before their biological significance was fully understood. The WOODS-FILDES theory that they exert their bacteriostatic action by competition with p-aminobenzoic acid, and the later recognition of this substance as a vitamin either by itself or as a component of pteroylglutamic acid, have now amply justified the classification of these well-known therapeutic agents as anti-vitamins.Artificial anti-vitamins opposing the actions of vitamins B1, C, E, K, nicotinic amide, "
-
riboflav ine, biotin, adermin, pantothenic acid, inositol, Some of the less important than p-a.minobenzoic acid for the nutrition of bacteria, but few of the anti-vitamins so far tested show promise of rivalling the sulphonamides in the treatment of infections. Their mode of action appears to depend on their close chemical similarity to the actual vitamins, which allowsthem to displace the vitamin in its association with essential enzyme systems, thus rendering these systems ineffective. Clearly, therefore, the artificial analogues must differ widely in their mode of action from most of thenaturally occurring antagonists,- which seldom bear a close chemical resemblance to the vitamins which they oppose. KODICEK contends that the term " toxamin should be applied to all substances which interfere with the action of vitamins, whereas " anti-vitamin should be reserved for the substances which act by reason of chemical analogy. On this basis dicoumarolwhich was discovered iii spoilt sweet clover through the severe outbreak 6f hæmorrhagic disease which it and
choline
have been
vitamins they antagonise
synthesised. are no
"
"
caused in
cattle, may reasonably naturally occurring anti-vitamin ;
be classed
as
a
and inoidentally the use of dicoumarol in the treatment of thrombosis is an instructive illustration of the application of veterinary research to human medicine. The existence of toxamins adds greatly to the perplexities of the analyst called on to estimate the vitamin values of a food. For most vitamins he has both chemical and biological methods of testing at his disposal. If he uses chemical tests he will learn how much of a particular vitamin is present, but he will not know whether the vitamin can be efficiently absorbed from the food or whether the food contains toxamins which will prevent the vitamin from exerting its full activity. A biological test, on the other hand will measure the total physiological activity of the food, as influenced by the efficiency of absorption of the vitamin and the presence or absence of toxamins, but will not tell him the actual amount of vitamin present. Measurements of vitamin contents " by chemical methods and of vitamin activities " by biological methods, therefore, may sometimes give widely divergent results. Neither result can be considered more essentially right than the other, and the choice will depend on the question which the analyst has set out to answer. To avoid ambiguity, data on the vitamin values of foods should be accompanied by an indication of the method of estimation used.
Histoplasmosis and Pulmonary
Tuberculosis
THE resemblance between tuberculosis and some fungus infections of the lung has long been recognised, particularly in the United States. Coccidioidomycosis, for example, can sometimes only be distinguished from tuberculosis by careful examination of the sputum and the specific skin-tests to tuberculin and coccidioidin : while torulosis, as DANIEL and his colleaguesi lately showed in these columns, can simulate tuberculosis of the nervous system very closely. No condition recognised by mycologists has given rise to such intense speculation within recent years as histoplasmosis, an infection with the fungus Histoplasma capsulatum, which is sometimes known as Darling’s disease," the acute form of which has been known since 1906. The early cases recorded-presented with fever, ulceration of the mouth and gastro-intestinal tract, enlargement of the liver, spleen, and lymphanaemia, and leucopenia. It was confused with kala-azar until the causative organism was found either in the blood or more often in affected tissue, particularly the lymph-glands and bonemarrow. Isolated reports appeared subsequently, but the real extent of the infection did not begin to be suspected until 1945, when CHRISTIE and his colleagues2 in Tennessee, after observing afatal case in a child, prepared histoplasmin, -a substance which on injection produced a specific skin reaction in people who had been infected with the fungus. Further studies showed that histoplasmin sensitivity that such sensitivity was unexpectedly common; was sometimes associated with pulmonary calcification, usually multiple and sometimes massive but often miliary in type;. and that many people With dis"
glands,
1. Daniel
P. M., Schiller, F., Vollum, R. L. Lancet, 2. Christie, A., Patterson, J. C. Amer. J. publ. Hlth,
Jan. 15, p. 53. 1945, 35, 1131.
229
pulmonary calcifications reacted positively to histoplasmin but not to tuberculin. Furthermore, sensitivity to histoplasmin seemed to be more or less confined to a rigid geographical area in the Middle West of the U.S.A. Since most of the histoplasmin reactors gave no past history of illness it is evident that infection with the fungus can occur in a subclinical form : there appears, in fact, to be a gradation in severity from the acute generalised histoplasmosis described by DARLING to the subclinical form, inferred from the results of skin testing. which may or may not be associated with multiple calcifications in the lung substance. For example, in five cases which came to necropsy HOLT3 has noted lung changes ranging from miliary parenchymatous lesions, with hilar lymph-glandular enlargement, to patchy pneumonitis and larger areas of pulmonary consolidation. The many writers on this subject in the last five years have emphasised the close similarity between histoplasmosis and tuberculous infection ; they have also cast doubt on the fairly general assumption that calcified deposits in the lung substance, symptomless and discovered accidentally by X ray, are always seminated
the result of tuberculosis. But calcification, even though symptomless, is the end-result of a previously active focus, and such foci in histoplasmosis have only rarely been recognised and studied. EDWARDS and colleagues4 have now tried to bridge this gap in a detailed and comprehensive study of the pulmonary infiltrates and mediastinal lymph-glands enlargement observed among 12,803 student nurses who were systematically tested for sensitivity to both tuberculin and histoplasmin. Of these nurses 224 showed pulmonary infiltrates, classified into (1) nodular, (2) poorly circumscribed, (3) fibrotic, and (4) " nonspecific " infiltrates, naturally of diverse aetiology. Only 0.26% of the infiltrates were found in the group which reacted to neither antigen. Further analysis revealed an association between the tvpe of infiltrate and the type of antigenic sensitivity. Thus, for nodular infiltrates, among nurses who reacted to histoplasmin alone the rate was 3.4%; whereas among the tuberculin reactors who did not react to histoplasmin it was 0-4%. The opposite was true of poorly circumscribed infiltrates, which were found in 1.9% of nurses who reacted to tuberculin alone compared with 0-4% of those reacting to histoplasmin alone. Other points of difference suggested by this survey were : first, that the poorly circumscribed infiltrates associated with a positive tuberculin reaction tended to occupy the upper parts of the lungs, whereas the nodular infiltrates found in histoplasmin reactors were universally distributed ; and secondly, that calcification seemed more common in the nodular .infiltrates of the histoplasmin reactors than in the other groups. Enlargement of the mediastinal lymph-glands was observed 38 times : 31 of these nurses reacted to histoplasmin alone, 4 to both antigens, and 3 to neither antigen. None reacted to tuberculin alone. These studies should ’not be regarded as supplying final proof, but they forcibly suggest that histoplasmosis in the United States is a disease to be ,reckoned with as a source of pulmonary calcification. On this side of the Atlantic the infection has not yet J. F. Amer. J. Roentgenol. 1947, 58, 717. Edwards. L. B., Lewis, I., Palmer, C. E. Publ. Wash. 1948, 63, 1569.
3. Holt, 4.
Hlth Rep.
been demonstrated, so far as we are aware : of several . hundred people living in Holland none were found to react to histoplasmin,5 and a, small investigation by McWEErrEY and his colleagueson 320 Dublin We must children was completely negative. nevertheless be on the watch.
Annotations THE WRONG DRUG
DOCTORS and nurses are still not always fully aware of the potency of the local anaesthetics they handle every day, and of the ease with which these drugs, improperly used, can kill. Distressing and needless deaths still occur in our hospitals-and not by any means only in the smallest ones-because a drug is injected either in mistake for another or in gross overdosage. One of the common mistakes is to inject a more potent local anaesthetic (the names of all of them end in " ... caine ") in the belief that it is procaine. The drug is injected in a dose many times its proper one, and the patient dies. Lately another such reporthas been added to the already long list of similar cases. A young man was to have a nasal operation. A liquid which the surgeon believed to be procaine was injected. It was in fact cocaine and the patient died. Once again the coroner expressed the hope that, to,avoid a repetition of this accident, drugs would be identified by distinctive colours and those responsible for them would be more careful. But neither publicity _ nor coroners’ admonitions have sufficed to prevent these distressing errors. The injection of cocaine instead of procaine is but one example of mistaken identity. Alcohol and thiopentone, as well as antiseptics of various kinds, have also been injected, instead of local anaesthetics, into nerves, with disastrous results. Even the fear of litigation, and the possibility of heavy damages such as have been imposed in another case of this nature,have not been effective. In the long run the only remedy lies in teaching medical students the dangers of these drugs and the dire results that follow their confusion. At present students, and even surgeons, receive little instruction on local anaesthetic drugs apart from what they are taught by professional pharmacologists early in’their career. It might be better if this information was given them shortly before their qualification by someone familiar with the drugs through
budding
daily
’
use.
In the case of local anaesthetics the two suggestions commonly put forward are for the solutions to be distinctively coloured, and for the names of the drugs to be so dissimilar in sound that they could not be confused even in the most indistinct telephone conversation. Either suggestion would undoubtedly help to prevent accidents if adopted on a national scale, with the backing of the British Pharmacopœia and defence societies, and if non-observance carried legal penalties. But many hospitals already colour their cocaine red ; and at least one death occurred because the pharmacist omitted to do so and the solution was assumed to be procaine. To reduce the chances of error precautions of this sort must be backed by a heightened awareness of the possibility for danger. It is still not uncommon, for example, to hearNupercaiiie’ referred to asPercaine ’ at scientific the -latter name was given up some meetings, though 9
because there had been confusion between and procaine. Then if cocaine, percaine, dangerous
six years ago
"
Quoted by Christie and Patterson. McWeeney, F. J., Crowe, M., J. med. Ass. Eire, 1846, 19, 163. 7. Manchester Guardian, Jan. 12, 1949. 8. Lancet, 1947, i, 571. 9. Ibid, 1942, ii. 221, 340.
5. 6.
Dunleavy, E.,
Magnon, M.
‘
when GOWLAND HOPKINS showed that diseases may be caused, without the intervention of toxic agents, merely by deficiency in nutrients needed in minute amounts. Later research, however, has indicated that the body’s requirements for aneurine (B1) are related to the carbohydrate intake ; and on this basis the starch in polished rice might be looked on as toxic to fowls suffering from aneurine deficiency. Apart from these early surmises, MELLANBY must be given full credit for the introduction and practical ’’ proof of the toxamin theory. About 20 years ago he found that dogs whose diets contained certain cereal products---$-particularly oatmeal-were abnormally liable to rickets. BRUCE and CALLOW subsequently showed that the anti-calcifying properties of cereals were due to the presence of phytic acid, which is a phosphorylated form of the vitamin inositol. HARRISON and MELLANBY confirmed that phytic acid had the same rachitogenic effects as cereals in dogs, while McCANCE reported that calcium metabolism was disturbed in human subjects subsisting on a diet consisting largely of wholemeal bread, which is rich in phytic acid. Investigations in many other fields have since demonstrated that a wide variety of natural substances may interfere with the action of different vitamins. Thus vitamins A and E are opposed by rancid fats,- vitamin E by cod-liver oil, vitamin K by dicoumarol present in spoilt sweet clover, vitamin B1 by some forms of raw fish and by substances present in ferns, nicotinic acid by maize, and biotin by the avidin present in raw egg-white. In addition to these natural antagonists many artificial anti-vitamins have been synthesised. The first representatives of this class to be discovered were the sulphonamides, which were used in infections before their biological significance was fully understood. The WOODS-FILDES theory that they exert their bacteriostatic action by competition with p-aminobenzoic acid, and the later recognition of this substance as a vitamin either by itself or as a component of pteroylglutamic acid, have now amply justified the classification of these well-known therapeutic agents as anti-vitamins.Artificial anti-vitamins opposing the actions of vitamins B1, C, E, K, nicotinic amide, "
-
riboflav ine, biotin, adermin, pantothenic acid, inositol, Some of the less important than p-a.minobenzoic acid for the nutrition of bacteria, but few of the anti-vitamins so far tested show promise of rivalling the sulphonamides in the treatment of infections. Their mode of action appears to depend on their close chemical similarity to the actual vitamins, which allowsthem to displace the vitamin in its association with essential enzyme systems, thus rendering these systems ineffective. Clearly, therefore, the artificial analogues must differ widely in their mode of action from most of thenaturally occurring antagonists,- which seldom bear a close chemical resemblance to the vitamins which they oppose. KODICEK contends that the term " toxamin should be applied to all substances which interfere with the action of vitamins, whereas " anti-vitamin should be reserved for the substances which act by reason of chemical analogy. On this basis dicoumarolwhich was discovered iii spoilt sweet clover through the severe outbreak 6f hæmorrhagic disease which it and
choline
have been
vitamins they antagonise
synthesised. are no
"
"
caused in
cattle, may reasonably naturally occurring anti-vitamin ;
be classed
as
a
and inoidentally the use of dicoumarol in the treatment of thrombosis is an instructive illustration of the application of veterinary research to human medicine. The existence of toxamins adds greatly to the perplexities of the analyst called on to estimate the vitamin values of a food. For most vitamins he has both chemical and biological methods of testing at his disposal. If he uses chemical tests he will learn how much of a particular vitamin is present, but he will not know whether the vitamin can be efficiently absorbed from the food or whether the food contains toxamins which will prevent the vitamin from exerting its full activity. A biological test, on the other hand will measure the total physiological activity of the food, as influenced by the efficiency of absorption of the vitamin and the presence or absence of toxamins, but will not tell him the actual amount of vitamin present. Measurements of vitamin contents " by chemical methods and of vitamin activities " by biological methods, therefore, may sometimes give widely divergent results. Neither result can be considered more essentially right than the other, and the choice will depend on the question which the analyst has set out to answer. To avoid ambiguity, data on the vitamin values of foods should be accompanied by an indication of the method of estimation used.
Histoplasmosis and Pulmonary
Tuberculosis
THE resemblance between tuberculosis and some fungus infections of the lung has long been recognised, particularly in the United States. Coccidioidomycosis, for example, can sometimes only be distinguished from tuberculosis by careful examination of the sputum and the specific skin-tests to tuberculin and coccidioidin : while torulosis, as DANIEL and his colleaguesi lately showed in these columns, can simulate tuberculosis of the nervous system very closely. No condition recognised by mycologists has given rise to such intense speculation within recent years as histoplasmosis, an infection with the fungus Histoplasma capsulatum, which is sometimes known as Darling’s disease," the acute form of which has been known since 1906. The early cases recorded-presented with fever, ulceration of the mouth and gastro-intestinal tract, enlargement of the liver, spleen, and lymphanaemia, and leucopenia. It was confused with kala-azar until the causative organism was found either in the blood or more often in affected tissue, particularly the lymph-glands and bonemarrow. Isolated reports appeared subsequently, but the real extent of the infection did not begin to be suspected until 1945, when CHRISTIE and his colleagues2 in Tennessee, after observing afatal case in a child, prepared histoplasmin, -a substance which on injection produced a specific skin reaction in people who had been infected with the fungus. Further studies showed that histoplasmin sensitivity that such sensitivity was unexpectedly common; was sometimes associated with pulmonary calcification, usually multiple and sometimes massive but often miliary in type;. and that many people With dis"
glands,
1. Daniel
P. M., Schiller, F., Vollum, R. L. Lancet, 2. Christie, A., Patterson, J. C. Amer. J. publ. Hlth,
Jan. 15, p. 53. 1945, 35, 1131.
229
pulmonary calcifications reacted positively to histoplasmin but not to tuberculin. Furthermore, sensitivity to histoplasmin seemed to be more or less confined to a rigid geographical area in the Middle West of the U.S.A. Since most of the histoplasmin reactors gave no past history of illness it is evident that infection with the fungus can occur in a subclinical form : there appears, in fact, to be a gradation in severity from the acute generalised histoplasmosis described by DARLING to the subclinical form, inferred from the results of skin testing. which may or may not be associated with multiple calcifications in the lung substance. For example, in five cases which came to necropsy HOLT3 has noted lung changes ranging from miliary parenchymatous lesions, with hilar lymph-glandular enlargement, to patchy pneumonitis and larger areas of pulmonary consolidation. The many writers on this subject in the last five years have emphasised the close similarity between histoplasmosis and tuberculous infection ; they have also cast doubt on the fairly general assumption that calcified deposits in the lung substance, symptomless and discovered accidentally by X ray, are always seminated
the result of tuberculosis. But calcification, even though symptomless, is the end-result of a previously active focus, and such foci in histoplasmosis have only rarely been recognised and studied. EDWARDS and colleagues4 have now tried to bridge this gap in a detailed and comprehensive study of the pulmonary infiltrates and mediastinal lymph-glands enlargement observed among 12,803 student nurses who were systematically tested for sensitivity to both tuberculin and histoplasmin. Of these nurses 224 showed pulmonary infiltrates, classified into (1) nodular, (2) poorly circumscribed, (3) fibrotic, and (4) " nonspecific " infiltrates, naturally of diverse aetiology. Only 0.26% of the infiltrates were found in the group which reacted to neither antigen. Further analysis revealed an association between the tvpe of infiltrate and the type of antigenic sensitivity. Thus, for nodular infiltrates, among nurses who reacted to histoplasmin alone the rate was 3.4%; whereas among the tuberculin reactors who did not react to histoplasmin it was 0-4%. The opposite was true of poorly circumscribed infiltrates, which were found in 1.9% of nurses who reacted to tuberculin alone compared with 0-4% of those reacting to histoplasmin alone. Other points of difference suggested by this survey were : first, that the poorly circumscribed infiltrates associated with a positive tuberculin reaction tended to occupy the upper parts of the lungs, whereas the nodular infiltrates found in histoplasmin reactors were universally distributed ; and secondly, that calcification seemed more common in the nodular .infiltrates of the histoplasmin reactors than in the other groups. Enlargement of the mediastinal lymph-glands was observed 38 times : 31 of these nurses reacted to histoplasmin alone, 4 to both antigens, and 3 to neither antigen. None reacted to tuberculin alone. These studies should ’not be regarded as supplying final proof, but they forcibly suggest that histoplasmosis in the United States is a disease to be ,reckoned with as a source of pulmonary calcification. On this side of the Atlantic the infection has not yet J. F. Amer. J. Roentgenol. 1947, 58, 717. Edwards. L. B., Lewis, I., Palmer, C. E. Publ. Wash. 1948, 63, 1569.
3. Holt, 4.
Hlth Rep.
been demonstrated, so far as we are aware : of several . hundred people living in Holland none were found to react to histoplasmin,5 and a, small investigation by McWEErrEY and his colleagueson 320 Dublin We must children was completely negative. nevertheless be on the watch.
Annotations THE WRONG DRUG
DOCTORS and nurses are still not always fully aware of the potency of the local anaesthetics they handle every day, and of the ease with which these drugs, improperly used, can kill. Distressing and needless deaths still occur in our hospitals-and not by any means only in the smallest ones-because a drug is injected either in mistake for another or in gross overdosage. One of the common mistakes is to inject a more potent local anaesthetic (the names of all of them end in " ... caine ") in the belief that it is procaine. The drug is injected in a dose many times its proper one, and the patient dies. Lately another such reporthas been added to the already long list of similar cases. A young man was to have a nasal operation. A liquid which the surgeon believed to be procaine was injected. It was in fact cocaine and the patient died. Once again the coroner expressed the hope that, to,avoid a repetition of this accident, drugs would be identified by distinctive colours and those responsible for them would be more careful. But neither publicity _ nor coroners’ admonitions have sufficed to prevent these distressing errors. The injection of cocaine instead of procaine is but one example of mistaken identity. Alcohol and thiopentone, as well as antiseptics of various kinds, have also been injected, instead of local anaesthetics, into nerves, with disastrous results. Even the fear of litigation, and the possibility of heavy damages such as have been imposed in another case of this nature,have not been effective. In the long run the only remedy lies in teaching medical students the dangers of these drugs and the dire results that follow their confusion. At present students, and even surgeons, receive little instruction on local anaesthetic drugs apart from what they are taught by professional pharmacologists early in’their career. It might be better if this information was given them shortly before their qualification by someone familiar with the drugs through
budding
daily
’
use.
In the case of local anaesthetics the two suggestions commonly put forward are for the solutions to be distinctively coloured, and for the names of the drugs to be so dissimilar in sound that they could not be confused even in the most indistinct telephone conversation. Either suggestion would undoubtedly help to prevent accidents if adopted on a national scale, with the backing of the British Pharmacopœia and defence societies, and if non-observance carried legal penalties. But many hospitals already colour their cocaine red ; and at least one death occurred because the pharmacist omitted to do so and the solution was assumed to be procaine. To reduce the chances of error precautions of this sort must be backed by a heightened awareness of the possibility for danger. It is still not uncommon, for example, to hearNupercaiiie’ referred to asPercaine ’ at scientific the -latter name was given up some meetings, though 9
because there had been confusion between and procaine. Then if cocaine, percaine, dangerous
six years ago
"
Quoted by Christie and Patterson. McWeeney, F. J., Crowe, M., J. med. Ass. Eire, 1846, 19, 163. 7. Manchester Guardian, Jan. 12, 1949. 8. Lancet, 1947, i, 571. 9. Ibid, 1942, ii. 221, 340.
5. 6.
Dunleavy, E.,
Magnon, M.
‘